Abstract
Thorough studies of previous analytical stress data of tetrabenazine, a dopamine depleting agent, showed a potential susceptibility to acidic conditions. Hence, the behavior of tetrabenazine acidic solutions was studied by LC-MS and NMR spectroscopy. Reverse-phase LC-MS analysis of tetrabenazine acidic aqueous solutions consistently showed a main lipophilic impurity in a proportion of 15 to 20%. NMR spectroscopy studies did not allow to completely ascertain its structure. However, we hypothesize an interconversion of trans-tetrabenazine with its unstable cis isomer via an open isoquinolinium intermediate. Evaluation of tetrabenazine integrity in orodispersible films was reassessed in light of these observations after formulation and during stability study. Even if interconversion of trans-tetrabenazine with its cis isomer was observed in orodispersible films containing tetrabenazine, this phenomenon seems not to have any consequences for the overall tetrabenazine bioavailability.
Highlights
Tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2one, TBZ, Xenazine®, Figure 1), a dopamine depleting agent, is clinically used to manage movement disorders like chorea associated with Huntington’s disease as well as off-label symptomatic treatment of many other hyperkinetic movement disorder [1,2,3]
Off-resonance ROESY (Rotating frame nuclear Overhauser effect spectroscopy) experiments were carried out according to Bax and Davis [20] and Desvaux et al [21]
A tetrabenazine sample (0.150 g, 0.473 mmol) was dissolved in 1.5 M citric acid/D2O solution (15 mL), and the solution was refluxed for 16 h under inert atmosphere
Summary
Tetrabenazine (3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2one, TBZ, Xenazine®, Figure 1), a dopamine depleting agent, is clinically used to manage movement disorders like chorea associated with Huntington’s disease as well as off-label symptomatic treatment of many other hyperkinetic movement disorder [1,2,3]. Valbenazine (Ingrezza®) [4,5,6], an isoleucine derivative of a tetrabenazine metabolite and deutetrabenazine (Austedo®), have been approved for treatment of same pathologies [7,8]. Deuterated drugs present as deutetrabenazine, the first approved deuterated drug, and have improved stability and better pharmacokinetics than their hydrogenated counterparts [9,10,11,12,13]. TTBBZZ,, ttwwoo tteettrraabbeennaazziinnee pphhoottoollyyttiicc iimmppuurriittiieess and valbenazine. Previous stability study of TBZ solution under Suntest® light exposure [14] has shown two majorPTreBvZioiumspsutarbitiileitsyisdteundtyifioefdTaBsZdseodluihtiyodnroutnedtrearbSeunnatzeisnte® l(iDghTtBeZx)paonsdurdee[t1e4t]rahhaysdshrootwetnratbweonmazainjoer (TTBTZBZim),pausrsioticeisatieddenttoifsietrdoansgddeidsichoylodrraottieotnra(bFeingauzriene1)(.DCTBloZs)eaenxdamdeitneatrtiaohnydorforteevtrearbsee-npahzainsee (LTCT-BMZS), cahsrsoomciaatteodgratmo ssrterovnegaleddisocnoeloardatdioitnion(aFligwueraek 1p)e. [F14w],asshionwveisntgigyaetelldowdiirnegctloyf aTfBteZr fionramquuleaotiuosnsaonludtidounrianfgtear ssttraobnilgityligsthutdeyxp(6osmuoren.thTsh,u4s0, ◦eCva, l7u5a%tioHnRo)fbTyBLZCi-nMteSg. rity in ODF was investigated directly after formulation and during a stability study (6 months, 40 °C, 75% HR) by LC- Tahqiusedoiuscsosloorluattiioonn h(caistrbiceenacciodr)r.elHatoedwweviethr,reyseullltoswoibntgainoefd bTyBZBouOrDezFg ewt aasl. [o1b4s],esrhvoedwindguyrienlglowstinabgiloiftyTBsZtuidniaeqs.ueTohuiss sdoilsuctoiolonraatfitoernshtraosnbgeleignhctoerxrpeloastuedre.wTihthusr,eesuvaltlsuoatbitoaninoefdTBbyZ Binotuegreriztgy eint aOlD. [F14w],asshionwveisntgigyaetelldowdiirnegctloyf aTfBteZr fionramquuleaotiuosnsaonludtidounrianfgtear ssttraobnilgityligsthutdeyxp(6osmuoren.thTsh,u4s0, ◦eCva, l7u5a%tioHnRo)fbTyBLZCi-nMteSg. rity in ODF was investigated directly after formulation and during a stability study (6 months, 40 °C, 75% HR) by LC-
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